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A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

ABSTRACT: Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum ?-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.).

SUBMITTER: Connolly LE

PROVIDER: S-EPMC5913993 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

Connolly Lynn E LE Riddle Valerie V Cebrik Deborah D Armstrong Eliana S ES Miller Loren G LG

Antimicrobial agents and chemotherapy 20180327 4

Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, ...[more]

PMID: 29378708

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Project description:BackgroundThe global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis.MethodsHospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia).ResultsOf 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidime-avibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, -2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone.ConclusionsCeftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting.Clinical trials registrationNCT01595438; NCT01599806.

Project description:BackgroundThe clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP).MethodsA combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP.FindingsEBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin.InterpretationThis study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Project description:Abstract Background Ceftriaxone–sulbactam–EDTA (CSE) is a novel combination being developed to treat serious infections caused by Gram-negative bacteria. In vitro molecular biology studies have shown that the addition of EDTA in the combination helps to prevent horizontal gene transfer during conjugation by chelating the divalent magnesium ions (Mg2+) required for the activity of DNA relaxases enzyme. An assessment of acquisition of resistant genes and a concomitant increase in MIC for patients that failed therapy in the Phase 3 clinical trial (NCT03477422) was conducted. Methods MICs were conducted on baseline and post-treatment isolates recovered during treatment period. MICs were determined using CLSI reference methods and MIC changes from baseline were further assessed. Bacterial DNA was extracted by the alkaline lysis method. ?-Lactamase (BL) genes were amplified in single PCRs using a panel of primers for detection of most ?-lactamase enzymes, including extended-spectrum ?-lactamases (ESBLs) (blaTEM, blaSHV, blaCTX-M), metallo-?-lactamases (MBLs) (blaVIM, blaNDM, blaIMP), carbapenemases (blaOXA, blaKPC) and class C cephalosporinases (blaAmpC). Results Nine of 143 [2/74 (2.7%) in CSE; 7/69 (10.1%) in MR (meropenem)] patients had a microbiological failure at the TOC visit. Of these nine patients (all E. coli), a variation in the post-treatment genotypic profile was noted for four patients (44.4%) in the MR group and two of these patients also reported a ?4-fold increase in post-treatment MIC. Both patients harbored four distinct BL genes (blaTEM + blaSHV + blaCTX-M + blaAmpC) at baseline, and had acquired two additional genes (blaOXA, blaKPC), both carbapenemases, as a result of treatment failure (after 6 days and 8 days of IV therapy respectively) with MR. In the first case, MIC increased 16-fold (1 µg/mL to 16 µg/mL for MR and 2 µg/mL to 32 µg/mL for CSE), while in the second case, MIC increased 8-fold (1 µg/mL to 8 µg/mL) for MR and 32-fold (1 µg/mL to 32 µg/mL) for CSE. No such increase in MIC or acquisition of resistant genes was noted in patients that failed therapy with CSE. Conclusion These findings highlight the need for an effective choice of empirical therapy as failed treatments could lead to selection for resistant genes, rendering once susceptible drug non-susceptible. Disclosures M. A. Mir, Venus Medicine Research Centre: Employee, Salary. S. Chaudhary, Venus Medicine Research Centre: Employee and Shareholder, Salary. M. Chaudhary, Venus Medicine Research Centre: Board Member and Shareholder, Salary. A. Pyasi, Venus Medicine Research Centre: Employee, Salary. R. Girotra, Venus Medicine Research Centre: Employee, Salary.

Dataset Information

A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

Publications

A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis.

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